The drug discovery of new anticancer agents has recently moved from cell-based assay to a more focused in vitro approach on well characterized, isolated and transfection assisted expressed proteins of druggable targets. This protein(s) targeted drug discovery paradigm is well described in the art with the large effort produced in the drug discovery field of the rational design of human kinase inhibitors allowing to explore the human kinome. Indeed, human kinase could be mutated and kinase deregulation usually take place in malignant transformation, growth and the ultimate metastasis evolution of human cancers. This kinase implication in the development and the proliferation of cancers is well establish in for example leukemia, lymphoma, non-small-cell lung cancer, melanoma, colon, breast, kidney, hepatocarcinoma . . . . Nowadays, despite this large effort to target human kinase dysfunctions in some cancers, the clinical breakthrough of the use of kinase inhibitor in anti-cancer therapy is not obviously associated with curing or remission, and several cancers seems to remain naturally resistant to the clinical use of kinase inhibitors (e.g. hepatocellular carcinoma). Moreover, the kinase inhibitors can select in vivo some mutated and resistant strains or the transformed cells can find equally compensating pathways. In this context, we decided to take into account the whole cell compartment and a cellular culture environment with the development of an unbiased phenotypic cellular screening assay. Moreover, the molecular understanding and the molecular description of cellular transformation, cancer growth and metastasis evolution is still remain in constant development, with for example the recent description of the cancer stem cells (CSCs) concept or tumor initiating cells (TICs). Unexpected effects in cellular screening may suggest other targets or specific interactions for the discovery of a new druggable target. Therefore, the development of new anticancer agents still remains a unique challenge with unpredictable outcome and a place for the discovery of new and innovative compounds.
The inventors have prepared a new series of diversity oriented of 2-primary amino-2-secondary amino-arylquinoline compounds library which was screened against a panel of human cancer cell lines (MOLM14, KG-1, MV4-11, A375, HCT116, HepG2, huh-7, MDA-MB-231, CAKI-1, 786-O) and patient-derived cancer primary cells allowing to discover novel anticancer agents. Moreover, this class of compounds shows equally an additional activity against human cancer stem cells (CSCs) which are widely incriminated in the recurrence and the relapse of cancers after anti-cancer therapy. A well describe in the art ALDH assay was used as cancer stem cell functional marker to describe the activity against CSCs (Greve, B. et al. Cytometry A 2012 (81) 284-293, Liu, S. et al. PLoS One 2013 (25) e81050, Ran, D. et al. Exp. Hematol. 2009 (37) 1423-1434, Cheung, A. M. et al. Leukemia 2007 (21) 1423-1430, Pearce, D. J. et al. Stem Cells 2005 (23) 752-760).
Therefore, it is an object of the present invention to provide active agents for preventing or inhibiting cell proliferation in a variety of organisms, and to provide methods for their synthesis.
It is another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of active agents of the invention, alone nor in combination with other active agents, and a pharmaceutically acceptable adjuvant, diluent or carrier.
It is another object of the present invention to provide active agents for use in therapy.
It is another object of the present invention to provide a method for the treatment and/or prevention of a proliferative and/or neoplastic disease.
It is another object of the present invention to provide a method for inhibiting the growth or differentiation of a Cancer Stem Cell (CSC), a tumor initiating cell, a mesenchymal-like cell associated with cancer, a mesenchymal cancerous cell, or a mesenchymal cell.